Particle sensor with wide linear range

Abstract

This invention provides a novel methods and devices for measurement of particle concentration or changes in particle concentration over a wide linear range. The invention comprises one or more radiation sources and one or more detectors contained in a housing which is interfaced to a medium containing particulate matter. The one or more radiation sources are directed into the medium, scattered or transmitted by the particulate matter, and then some portion of the radiation is detected by the one or more detectors. Methods for confining the measurement to a specific volume within the medium are described. Algorithms are provided for combining the signals generated by multiple source-detector pairs in a manner that results in a wide linear range of response to changes in particle concentration. In one embodiment the sensor provides non-invasive measurements of biomass in a bioreactor. In another embodiment an immersible probe design is described, which may be suited for one-time use. In an addition embodiment, a sensor is provided which is well suited to the rapid sequential measurement of particle concentration in multiple vessels, such as assessment of biomass in series of shake flasks.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is related to, and claims benefit of, U.S. Provisional Patent Application Ser. No. 60 / 962,350 filed Jul. 28, 2007, the disclosure of which is incorporated herein by reference in its entirety for all purposes.FIELD OF INVENTION[0002]The present invention relates generally to methods and devices for determining particle concentration in a medium through use of radiation sensors and detectors and algorithms to extend the linear range between particle concentration and radiation attenuation. Specific embodiments of the invention relate to biomass and growth rate monitoring using optical scattering or transmission to measure the concentration or rate of change of growth of cells or microorganisms in liquid cultures.BACKGROUNDRadiation Sensors for the Measurement of Particle Concentration[0003]In various media the dynamic range of particle concentration that can be measured by typical radiation sensors is limited by the non-lin...

AI Technical Summary

Benefits of technology

[0015]In yet other embodiments of the invention, the sensor is designed to be manually placed in close proximity to a vessel, such as a shake flask. A rapid measurement of particle concentration can be activated by contact with the vessel. In such manner, many vessels can be measured in rapid succession. Methods for ensuring alignment of the sensor optics relative to the vessel are provided. Further, methods for reducing sensitivity to thickness of the container wall are also provided.

Problems solved by technology

On the other hand, when the mean distance between particles is small compared to the distance between the source and detector, the effect of adding more particles will be non-additive due to multiple scattering and the screening effect of particles aligned along the same radiation path.

However, even in such attempts the range of linearity that is achieved is still too limited for many applications.

Furthermore, the optical arrangement required to measure both transmission and reflectance would make it difficult or impossible to conduct measurements non-invasively in many applications.

For example, cells can be genetically modified to produce high yields of chemicals that would otherwise be difficult, expensive, or impossible to synthesize.

Unfortunately, the non-linear response of currently available sensors to biomass, makes accurate estimation of growth rate difficult or impossible.

As the nutrient supply relative to the biomass diminishes, the growth of cell culture will slow.

Unfortunately, methods of continuously and reliably measuring the growth of cells or microorganisms in liquid cultures are not very robust, especially over a wide range of concentrations.

This method has several disadvantages: (1) each time liquid is withdrawn, there is a risk that the culture will be contaminated, (2) the method is not continuous, and (3) the method is labor intensive, requiring frequent extraction and precise volumetric dilution of the extracted liquid (especially when high cell concentrations are measured).

Unfortunately, such devices are prone to drift, particularly due to growth of cells or microorganisms on the sensor itself.

In addition, the range of biomass that can be measured is severely limited by the use of fixed path length transmission or reflectance measurements.

In general, prior attempts to non-invasively measure biomass have been limited by the linear range of response between a measured signal (e.g., light transmission through the culture) and concentration / biomass of the culture, or by sensitivity to vessel wall thickness.

However, the sensor response is highly non-linear with changes in concentration of cells.

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